Escaping the Phylogenetic Trap: Persistent Homology Enables Cross-Species Ion Channel Classification via Multimodal Graph Neural Networks

Arezoo Bybordi, Favour Achimba, Mariam Gelashvili, Jessy Ramirez, Weigang Qiu +2

Protein classifiers are highly sensitive to evaluation protocol: random train/test splits induce phylogenetic leakage, allowing models to exploit taxon-specific correlations and substantially overestimate out-of-distribution performance. This issue is particularly acute for venom compound classification by ion-channel target (Ca2+, K+, Na+), where reported accuracies of 80-90% do not reflect generalization to unseen taxa. We formulate cross-species prediction as a structured distribution shift in which taxonomic identity acts as a confounder, requiring representations that capture structural features invariant across phylogeny. Using a shared multimodal backbone that fuses ESM-2 sequence embeddings with a disulfide-aware graph attention network, we systematically compare five structural inductive biases (spectral, Riemannian, SE(3)-invariant, statistical-manifold, and persistent-homology representations) under a leave-one-taxon-out evaluation protocol on a benchmark of 1,373 ColabFold-predicted venom compounds spanning five taxa. The persistent-homology representation summarizes backbone geometry through topological descriptors that are robust to local structural perturbations,…